Posterior predictive checks of coalescent models: P2C2M,an R package

Bayesian inference operates under the assumption that the empirical data are a good statistical fit to the analytical model, but this assumption can be challenging to evaluate. Here, we introduce a novel r package that utilizes posterior predictive simulation to evaluate the fit of the multispecies coalescent model used to estimate species trees. We conduct a simulation study to evaluate the consistency of different summary statistics in comparing posterior and posterior predictive distributions, the use of simulation replication in reducing error rates and the utility of parallel process invocation towards improving computation times. We also test P2C2M on two empirical data sets in which hybridization and gene flow are suspected of contributing to shared polymorphism, which is in violation with the coalescent model: Tamias chipmunks and Myotis bats. Our results indicate that (i) probability‐based summary statistics display the lowest error rates, (ii) the implementation of simulation replication decreases the rate of type II errors, and (iii) our r package displays improved statistical power compared to previous implementations of this approach. When probabilistic summary statistics are used, P2C2M corroborates the assumption that genealogies collected from Tamias and Myotis are not a good fit to the multispecies coalescent model. Taken as a whole, our findings argue that an assessment of the fit of the multispecies coalescent model should accompany any phylogenetic analysis that estimates a species tree.     

Earth Mover’s Distance (EMD): A True Metric for Comparing Biomarker Expression Levels in Cell Populations

Changes in the frequencies of cell subsets that (co)express characteristic biomarkers, or levels of the biomarkers on the subsets, are widely used as indices of drug response, disease prognosis, stem cell reconstitution, etc. However, although the currently available computational “gating” tools accurately reveal subset frequencies and marker expression levels, they fail to enable statistically reliable judgements as to whether these frequencies and expression levels differ significantly between/among subject groups. Here we introduce flow cytometry data analysis pipeline which includes the Earth Mover’s Distance (EMD) metric as solution to this problem. Well known as an informative quantitative measure of differences between distributions, we present three exemplary studies showing that EMD 1) reveals clinically-relevant shifts in two markers on blood basophils responding to an offending allergen; 2) shows that ablative tumor radiation induces significant changes in the murine colon cancer tumor microenvironment; and, 3) ranks immunological differences in mouse peritoneal cavity cells harvested from three genetically distinct mouse strains.     

Effect of Broccoli Sprouts and Live Attenuated Influenza Virus on Peripheral Blood Natural Killer Cells: A Randomized,Double-Blind Study

Enhancing antiviral host defense responses through nutritional supplementation would be an attractive strategy in the fight against influenza. Using inoculation with live attenuated influenza virus (LAIV) as an infection model, we have recently shown that ingestion of sulforaphane-containing broccoli sprout homogenates (BSH) reduces markers of viral load in the nose. To investigate the systemic effects of short-term BSH supplementation in the context of LAIV-inoculation, we examined peripheral blood immune cell populations in non-smoking subjects from this study, with a particular focus on NK cells. We carried out a randomized, double-blinded, placebo-controlled study measuring the effects of BSH (N = 13) or placebo (alfalfa sprout homogenate, ASH; N = 16) on peripheral blood mononuclear cell responses to a standard nasal vaccine dose of LAIV in healthy volunteers. Blood was drawn prior to (day-1) and post (day2, day21) LAIV inoculation and analyzed for neutrophils, monocytes, macrophages, T cells, NKT cells, and NK cells. In addition, NK cells were enriched, stimulated, and assessed for surface markers, intracellular markers, and cytotoxic potential by flow cytometry. Overall, LAIV significantly reduced NKT (day2 and day21) and T cell (day2) populations. LAIV decreased NK cell CD56 and CD158b expression, while significantly increasing CD16 expression and cytotoxic potential (on day2). BSH supplementation further increased LAIV-induced granzyme B production (day2) in NK cells compared to ASH and in the BSH group granzyme B levels appeared to be negatively associated with influenza RNA levels in nasal lavage fluid cells. We conclude that nasal influenza infection may induce complex changes in peripheral blood NK cell activation, and that BSH increases virus-induced peripheral blood NK cell granzyme B production, an effect that may be important for enhanced antiviral defense responses.Trial Registration: ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01269723","term_id":"NCT01269723"}}NCT01269723     

Arrival times,laying dates,and reproductive success of Snowy Plovers in two habitats in coastal northern California

ABSTRACT Habitat quality, as indexed by the reproductive success of individuals, can greatly influence population growth, especially for rare species near the limits of their range. Along the Pacific coast, the Snowy Plover (Charadrius alexandrinus nivosus) is a threatened species that, in recent years, has been breeding on both riverine gravel bars and ocean beaches in northern California. From 2001 to 2009, we compared the habitat characteristics, breeding phenology, reproductive success, and abundance of Western Snowy Plovers occupying these two habitats. Similar percentages of yearling and adult plovers returned to gravel bars and beaches, but plovers breeding on gravel bars arrived and initiated first clutches 2–3 weeks later than those breeding on beaches. Despite this delay, however, the mean annual fledging success of plovers on gravel bars (1.4 ± 0.4 [SD]) was double that on beaches (0.7 ± 0.3). Differences in cumulative reproductive success produced a stronger pattern. By their sixth year, males on gravel bars had fledged 14.5 ± 2.1 chicks, more than four times the number of young fledged by males on beaches (3.3 ± 3.1). Over 9 years, local population size decreased by about 75%, coincident with a shift in breeding distribution away from high‐quality gravel bars to ocean beaches. This unexpected population decline and shift to poorer quality beaches may have been related to occasional low survival of plovers that over‐winter exclusively on beaches in our study area. Consistently low productivity of plovers breeding on ocean beaches suggests the need for intensified management to ameliorate the negative impacts of predation and human activity on the recovery of this population.     

Discovery of SAR184841, a potent and long-lasting inhibitor of 11β-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D

Starting from 11β-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11β-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.     

Packed-Bed Bioreactors Under the Influence of Chemical Modulators

This report considers the behaviour of packed-bed immobilized enzyme reactors operating in the presence of substrate and/or product sequestrators. In some cases, enzyme inhibition by the reaction product and presence of chemical modulators are also considered. For each case, an appropriate analytical model is developed. Using numerical simulations, it is shown that reactor performance is impaired by substrate sequestration. This effect can be partially reversed when competitive sequestration by product or modulator is operational.

In addition, a comparison is made between some of the predicted characteristics of the reactor and experimental data. It reveals the capabilities and limitations of the models employed.     

Digestion of starch and glycaemic response to mixed meals in pigs.

The digestion in the proximal intestine of mixed meals (5,160 kJ) containing either native (NS) or pregelatinized (PS) maize starches (approximately 200 g), and the postprandial glycaemic responses they induced were compared in pigs. For both meals, approximately 25% of the ingested starch was assimilated above the duodenal cannula (positioned 75 cm beyond the pylorus). Larger amounts of starch were collected for NS than for PS during the first 30 min. The glycaemic responses, however, indicated a higher rate of glucose absorption for PS during the first 30 min, which could be explained by the higher susceptibility of PS to hydrolysis, as we observed in vivo. Indeed, malto-oligosaccharides (G1-G3) represented almost 80% of the total alpha-glucans collected at 150 min in the duodenum after the PS meal. At that time, after the NS meal, only 30% of the alpha-glucans were malto-oligosaccharides. Thus, even after a mixed meal, the starch digestion rate can alter the observed postprandial glycaemic response.     

Immunity to rubella in women of childbearing age in the United Kingdom.

In the first three years of a surveillance scheme for susceptibility to rubella in women aged 15-44 the results of over 1.3 million serological tests were collected by 80 laboratories throughout the United Kingdom. Seventy eight per cent of the results, or an average of 340,000 a year, were from pregnant women, so that just under half of all pregnant women in the United Kingdom were reported on. Eighteen per cent of results were from women tested before vaccination and the remainder were from diagnostic and other tests. Pregnant women showed an overall downward trend in susceptibility to rubella (from 4.2% at the beginning of 1984 to 3.0% at the end of 1986), and a similar decline was seen in the two other categories. Regional data showed a significant negative correlation between the proportion of pregnant women aged 15-19 who were susceptible to the virus and rate of uptake of vaccine in 14 year old schoolgirls. Women aged 25-29 were least susceptible. This form of laboratory surveillance is feasible and representative; it should be continued to monitor the effect of introducing the measles, mumps, and rubella vaccine.